Mr. Chairman, and Members of the Subcommittee, it is a
pleasure to be here today to discuss the recent scientific
advances in genetics that will lead to improved health,
and the development of therapies to treat various illnesses.
First I would like to thank the Subcommittee, and especially
you Mr. Chairman and Ranking Member Specter, for your commitment
and determination to invest in the Human Genome Project
and other areas of basic biomedical research at the National
Institutes of Health. Today I would like to focus my remarks
on the recent developments in genetics in order to give
you a sense of the great promise this field of research
holds for all of us. Today you will also hear from patients
and advocates who are fighting to find a cure for genetic
diseases. All of us have gained a powerful new set of tools
from the recent advances in human genetic research. As a
physician who has taken care of patients, and as a medical
geneticist who has devoted the last decade to the Human
Genome Project, I know it is critical that we move the great
promise of basic research into the clinic as quickly as
possible, in order to make significant progress towards
treating or preventing these devastating illnesses.

Human Genome Sequence

Last year, Human Genome Project scientists capped their
achievements of the last decade with a historic milestone
– the complete initial reading of the text of our genetic
instruction book. This book is written in an elegant digital
language, using a simple four-letter alphabet where each
letter is a chemical base, abbreviated A, C, G, or T. At
present, more than 95% of the 3.1 billion bases of the human
genome are freely available in public databases. This is
an awesome step toward a comprehensive view of the essential
elements of human life, a perspective that inaugurates a
new era in medicine where we will have a more profound understanding
of the biological basis of disease and develop more effective
ways to diagnose, treat, and prevent illness.

Between March 1999 and June 2000 the international
collaborators in the Human Genome Project sequenced DNA
at a rate of 1000 bases per second, 7 days a week, 24 hours
a day. After completing the working draft of the human genome
sequence in June of 2000, Human Genome Project scientists
and computational experts scoured the sequence for insights.
They reported the first key discoveries in the February
15, 2001 issue of the journal Nature. Among the findings
were the following:

Humans are likely to have only 30,000 to 40,000 genes,
just twice as many as a fruit fly, and far fewer than
the 80,000 to 150,000 that had been widely predicted.

Genes are unevenly distributed across the genomic landscape;
they are crowded in some regions and spread out widely
in others.

Individual human genes are commonly able to produce
several different proteins.

The repetitive DNA sequences that make up much of our
genome, and commonly regarded as "junk," have
been important for evolutionary flexibility, allowing
genes to be shuffled and new ones to be created. The repetitive
DNA may also perform other important functions, and provides
fascinating insights into history.

Finishing the human genome sequence

Because of the enormous value of DNA sequence information
to researchers around the world, in academia and industry,
the public Human Genome Project (HGP) has always been committed
to the principle of free, rapid access to genomic information
through well-organized, annotated databases. Databases housing
the human genome sequence are being visited by tens of thousands
of users a day. Over the coming two years, the HGP will
increase the usefulness of the human genome sequence to
the world’s researchers by finishing the sequencing to match
the project’s long-standing goals for completeness and stringent
accuracy. More than 40% of the draft sequence, including
two of our 24 chromosomes, have already been finished into
a highly accurate form – containing no more than 1 error
per 10,000 bases. Finished sequence for the entire genome
is expected by 2003.

Human genetic variation

While the DNA sequence between any two individuals
is 99.9% identical, that still leaves millions of differences.
For understanding the basis of common diseases with complex
origins, like heart disease, Alzheimer disease, and diabetes,
it is important to catalog genetic variations and how they
correlate with disease risk. Most of these are single letter
differences referred to as Single Nucleotide Polymorphisms
(SNPs). With a draft of the human genome sequence in hand,
the pace of SNP discovery has increased dramatically. In
FY 1999, NHGRI organized the DNA Polymorphism Discovery
Resource consisting of 450 DNA samples collected from anonymous
American donors with diverse ethnic backgrounds. NHGRI has
funded studies looking for SNPs in these samples. The non-profit
SNP Consortium came into being in April 1999, with the goal
of developing a high-quality SNP map of the human genome
and of releasing the information freely. Consortium members
now include the Wellcome Trust, a dozen companies (mostly
pharmaceutical companies), three academic centers, and NIH.
This has been remarkably successful, with 5 times more SNPs
being contributed to the public domain than the consortium
originally planned. As of June 22, the public database that
serves as a central repository for SNPs has received 2,972,764
SNP submissions.

With the increased knowledge about human variation,
the genetic underpinnings of various diseases, including
diabetes, are being discovered. The recent discovery of
a gene, calpain-10, whose disruption contributes to diabetes,
resulted from studies linking diabetes with genetic variations
across the whole genome and then in a specific part of chromosome
2. The newly-discovered gene variant suggests that a previously
unknown biochemical process is involved in the regulation
of blood sugar levels.

Gene expression

The new-found abundance of genomic information and
technology is propelling scientists out of the pattern of
studying individual genes and into studying thousands at
a time. Large-scale analyses of when genes are on or off
(gene expression) can be used, for example, to study the
molecular changes in tumor cells. This exciting new approach
combines recombinant DNA and computer chip technologies
to produce microarrays or DNA chips. Classifying cancer
on a molecular level offers the possibility of more accurate
and precise diagnosis and treatment. Intramural researchers
at NHGRI have used large-scale expression studies to discover
genetic signatures that can distinguish the dangers from
different skin cancers, and that can distinguish between
hereditary and sporadic forms of breast cancer.

Protein structure, function, and interaction

We must remember that we are at the beginning of genomics
era, not the end. With a global view of human genes now
possible, scientists are eager to obtain a similarly comprehensive
view of human proteins, a field called "proteomics." Researchers
want to know the functions of proteins and how the proteins
work together in cells. Only a subset of all possible proteins
are present in any given cells at any given time. To study
protein function on a wide scale, various groups of researchers
plan to identify the locations of proteins, their levels
in different cells, their structures, the interactions among
different proteins, and how they are modified. NHGRI is
contributing to this field by developing technologies for
efficient, large-scale analyses, particularly for determining
protein interactions and measuring protein abundance in
different cells.

Promise for new treatments and prevention

With the availability of a comprehensive view of our
genes, genetic testing will become increasingly important
for assessing individual risk of disease and prompting programs
of prevention. An example of how this may work involves
the disease hereditary hemochromatosis (HH), a disorder
of iron metabolism affecting about one in 200 to 400 Americans.
Those with the condition accumulate too much iron in their
bodies, leading to problems like heart and liver disease
and diabetes. The gene causing the condition has been identified,
allowing early identification of those in whom HH may develop.
Once people at risk are identified by genetic testing they
can easily be treated by periodically removing some blood.
The NHGRI and NHLBI are engaged in a large-scale project
to determine the feasibility of screening the adult population
for this very preventable disorder.

Genetic testing is also being used to tailor medicines
to fit individual genetic profiles, since drugs that are
effective in some people are less effective in others and,
in some, cause severe side effects. These differences in
drug response are genetically determined. Customizing medicine
to a patient’s likely response is a promising new field
known as pharmacogenomics. For example, a recent publication
in the journal Hypertension showed how pharmacogenomics
applies to high blood pressure. Researchers found a variation
in a particular gene that affects how patients respond to
a commonly used high blood pressure drug, hydrochlorothiazide.
Other recent studies reveal that doctors should avoid using
high doses of a common chemotherapy treatment (6-mercaptopurine)
in a small proportion of children with leukemia. Children
with a particular form of a gene (TPMT) suffer serious,
sometimes fatal, side effects from the drug.

Genomics is also fueling the development of new medicines.
Several drugs now showing promising results in clinical
trials are "gene-based" therapies, where an exact
appreciation of the molecular foundations of disease guides
treatment design. One of the first examples is Gleevec (previously
called STI571), produced by Novartis for treating chronic
myelogenous leukemia (CML), a form of leukemia that mostly
affects adults. CML is caused by a specific genetic flaw
– an unusual joining of chromosomes 9 and 22 producing an
abnormal fusion gene that codes for an abnormal protein.
The abnormal fusion protein spurs uncontrolled growth of
white blood cells. Novartis designed a small molecule that
specifically inactivates that protein. In phase I clinical
trials, this drug caused dramatically favorable responses
in patients, while side effects were minimal. By targeting
the fundamental biochemical abnormality associated with
this form of cancer, rather than killing dividing cells
indiscriminately as most chemotherapy does, the drug offers
better treatment results and fewer toxic effects on normal
cells. In May 2001, FDA approved Gleevec (imatinibmesylate,
also known as STI-571) for the treatment of Chronic Myeloid
Leukemia after a review time of less than three months.
Meanwhile, Bayer and Millennium announced the development
of another cancer drug born of genomics in January 2001.
GlaxoSmithKline is testing a new genomics-derived heart
disease drug that targets a protein involved in fat metabolism.
Johnson&Johnson is testing a drug targeting a brain
receptor identified through genomics, and involved with
memory and attention. Human Genome Sciences has four clinical
trials in progress to test gene-based drug candidates.

Ethical, Legal, and Social Implications

From its inception, NHGRI recognized its responsibility
to address the broader implications of having access to
genetic information and technology. Since the inception
of the Human Genome Project Congress has provided funds
for research to study the ethical, legal, and social implications
(ELSI) of genome research. To that end one of the greatest
areas of concern has been in the area of genetic discrimination.
Recently President Bush addressed this issue in his Saturday
radio address of June 23. In that address the President
said, "Just a few months ago, scientists completed the mapping
of the human genome. With this information comes enormous
possibilities for doing good. As with any other power, however,
this knowledge of the code of life has the potential to
be abused. Genetic discrimination is unfair to workers and
their families. It is unjustified -- among other reasons,
because it involves little more than medical speculation
.…To deny employment or insurance to a healthy person based
only on a predisposition violates our country's belief in
equal treatment and individual merit.… Just as we have addressed
discrimination based on race, gender and age, we must now
prevent discrimination based on genetic information. My
administration is working now to shape the legislation that
will make genetic discrimination illegal. I look forward
to working with members of Congress to pass a law that is
fair, reasonable, and consistent with existing discrimination
statutes."

Predictions for the Future

We must not ignore the ethical, legal, social, and
the commercial issues that genetic research raises, but
the promise of this research is great for alleviating human
suffering. If research continues to proceed vigorously,
we can expect medicine to be transformed dramatically in
the coming decades.

We can predict that by the year 2010, predictive genetic
tests will exist for many common conditions where interventions
can alleviate inherited risk; successful gene therapy will
be available for a small set of conditions; and primary
care providers will be practicing genetic medicine on a
daily basis. By the year 2020, gene-based designer drugs
are likely to be available for conditions like diabetes,
Alzheimer's disease, hypertension, and many other disorders;
cancer treatment will precisely target the molecular fingerprints
of particular tumors; genetic information will be used routinely
to give patients appropriate drug therapy; and the diagnosis
and treatment of mental illness will be transformed. By
the year 2030, we predict that comprehensive, genomics-based
health care will become the norm, with individualized preventive
medicine and early detection of illnesses by molecular surveillance;
gene therapy and gene-based therapy will be available for
many diseases; and a full computer model of human cells
will replace many laboratory experiments.